The dramatic progress in identifying cellular signaling pathways capable of modulating aging over the past two decades is largely due to the use by biogerontologists of model invertebrates (worms, and flies) that are easily mass cultured in the laboratory, short-lived, easily manipulated and observed, and genetically tractable. Despite their demonstrable utility, these species have certain limitations however, among which are their reasonably close evolutionary affinity with one another, extensive gene loss in their evolutionary lineages, and a limited ability to regenerate damaged tissues. Of particular note, a more distant ancestor to the vertebrates, the Cnidaria, have been discovered to contain a large number of obvious humans orthologs that are missing in the worm and fly genomes. This suggests the desirability of developing judiciously chosen new invertebrate species for aging research that would allow investigation of this previously invisible universe of potentially senescence-modulating genes. The general hypothesis which informs this proposal is that such new invertebrate models will provide insights into novel pathways and mechanisms for modulating aging. Specifically, we propose to develop hydras in this context. Hydra are small freshwater cnidarians which have been the subject of laboratory experimentation for more than 250 years. Their advantages include: (1) techniques for their mass laboratory culture are well developed; (2) they possess phenotypic traits to allow some assessment of their age-related health status (e.g. facility at prey capture and transfer to the gastric cavity, reproductive rate, regeneration capability); (3) they represent a basal evolutionary lineage of multicellular animals that shares genes with humans that are missing from worms and flies; (4) they exhibit both nonaging and rapidly aging phenotypes, which could represent a particularly informative comparison; (5) genomic resources for their study are rapidly becoming available, and (6) they have proven amenable to modern genetic manipulation, including RNAi knockdown, knock-in transgenesis, and the expression of reporter constructs. The proposed research represents a new collaboration between an investigator with expertise in the biology of aging and the development of nontraditional species for aging research and one with expertise in all aspects of hydra biology. In order to develop hydra for aging research by pursuing the following specific aims: (1) optimize experimental conditions for demographic analysis of hydra degenerative phenotypes and characterize the resultant demographic parameters in aging and putatively nonaging phenotypes; (2) assess genome and proteome stability of nonaging and aging phenotypes under basal and stressed conditions; (3) characterize and contrast by gene expression profiling and ultra high throughput sequencing the transcriptome of aging and nonaging phenotypes. and (4) screen by RNAi knockdown, large numbers of genes for their impact on hydra health and longevity. In sum, these aims should position hydra as a major contributor to aging research in the coming years. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine mechanisms that retard aging with the long-term goal of the development of therapies to slow human aging, thereby enhancing and preserving human health. Because aging is the ultimate cause of many late life maladies, the research has the potential to not only enhance health but delay and mitigate numerous late life diseases.